Action Points

Note that the company studying the drug holds patents to develop several chemical mitochondrial uncouplers, including niclosamide, and would like to begin trials in humans once federal regulators approve them.

Oral niclosamide ethanolamine salt (NEN) increased energy expenditure and lipid metabolism in C57 mice, and it also proved efficacious for preventing and treating hepatic steatosis and insulin resistance induced by a high-fat diet.

In a mouse model of type 2 diabetes, the drug was shown to improve glycemic control and delay disease progression, researcher Shengkan Jin, PhD, of Rutgers University-Robert Wood Johnson Medical School in Piscataway, N.J., and colleagues wrote in Nature Medicine, published online Oct. 5.

Jin told MedPage Today that his start-up company, Mito Biopharm, has patents to develop several chemical mitochondrial uncouplers, including NEN. Jin and colleagues are currently conducting toxicology studies of NEN to submit to the FDA, and they hope to begin trials in humans once federal regulators approve them.

"Uncoupling mitochondria to burn excess fat is a fascinating idea, but the challenge has been to find a practical and safe way to do this," he said, adding that the researchers focused on niclosamide because the drug's mechanism of action is to uncouple the mitochondria of parasitic worms and because the drug has a good safety profile.

Mitochondrial Uncoupling in Liver Promising T2D Target

Current therapies for type 2 diabetes treat the symptoms of the disease, but do not address the underlying cause of insulin resistance in peripheral tissue, and patients often become refractory to treatment, the researchers noted.

"Development of new anti-diabetic drugs with new mechanisms of action, in particular those targeting the cause of insulin resistance, is important to improve diabetes therapy," they wrote.

Although it is not entirely clear how lipid accumulation leads to insulin resistance and type 2 diabetes, it is increasingly clear that fat accumulation in the liver and muscles plays a major role, Jin noted.

"If we can get rid of fat accumulated in the liver and muscle, we can potentially cure type 2 diabetes," he said.

Mitochondrial uncouplers reduce the proton gradient across the mitochondrial inner membrane, creating a futile cycle of glucose and fatty acid oxidation without generating ATP. Transgenic mouse models that express mitochondrial uncoupling proteins in the liver or muscle have been shown in several studies to exhibit elevated fatty acid oxidation and reduced intracellular lipid accumulation. They also showed significant resistance to weight gain induced by feeding a high-fat diet and were protected from diet-induced insulin resistance.

"The effect of mitochondrial uncoupling on reducing intracellular lipid accumulation prompted us to search for safe mitochondrial uncouples and evaluate their potential use for type 2 diabetes treatment," the researchers wrote.

They noted that the best known chemical mitochondrial uncoupler is 2,4-dinitrophenol (DNP), which was used as a weight-loss drug in the 1930s. The drug did increase metabolic rates and promoted weight loss, but it was withdrawn from the market because it caused hyperthermia, tachycardia, and other adverse effects at high doses. A 2011 review identified 62 deaths related to DNP.

NEN Showed Good Safety Profile in Animals

The salt form of niclosamide has been studied extensively in animals, and long-term oral treatment of high doses of NEN (ranging from months to over a year) did not show adverse effects in mammals, including rats and dogs.

To test the anti-diabetes properties of the drug, Jin and colleagues first conducted pharmacokinetic and tissue distribution studies in NEN-treated C57BL/6J mice. These studies revealed that NEN is distributed primarily to the liver, with relatively high levels of metabolite present in the kidney and low or negligible levels in other tissue.

To examine the metabolic effect of oral NEN, the researchers fed one group of mice high-fat diets (HFD) alone and another group HFD with NEN at levels well below those shown to have adverse effects. The NEN-fed mice showed a higher energy expenditure rate and they exhibited a higher oxygen consumption rate, a marginally higher carbon dioxide production rate, and a lower respiration quotient, indicative of a larger proportion of energy expenditure derived from lipid oxidation.

No difference was seen between the NEN-treated and untreated mice, however, in body temperature.

In a series of experiments in both diet-induced diabetic mice and genetically engineered diabetic (db/db) mice, treatment with NEN proved efficacious for preventing and treating hepatic steatosis and insulin resistance, and it also improved glycemic control.

To determine the mechanism by which NEN improves glycemic control, the researchers compared the organs and tissues of mice fed either HFD alone or HFD containing NEN.

"Consistent with the fact that NEN is distributed primarily to the liver after oral treatment, the most striking difference between the two groups of mice was the size and appearance of the liver," the researchers wrote.

To investigate whether oral NEN could improve hepatic steatosis after the condition has been established, the researchers fed the mice HFD for 4 months and then switched to HFD containing NEN. Histological analyses and lipid content quantification showed that NEN treatment correlated with a lower degree of lipid accumulation in the liver, even though the mice were still on HFD.

DNP Derivative Also Increased Liver Fat Oxidation

The study is not the first to demonstrate that the beneficial effects of promoting mitochondrial uncoupling in the liver to increase hepatic fat oxidation can be accomplished without treatment-limiting toxicity, the researchers noted.

In a 2013 study, researchers reported the reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted derivative of DNP which did not induce treatment-limiting toxicity.

Jin and colleagues noted that their results are consistent with the model that NEN improves insulin sensitivity through mitochondrial uncoupling in the liver and the consequent reduction of hepatic lipid accumulation, and through secondary effects on muscle and adipose tissue.

Although the exact molecular mechanism driving this action is unclear, the researchers concluded that it is likely the AMPK-ACC pathway is involved in the upregulation of lipid oxidation triggered by mitochondrial uncoupling.

"Activation of AMPK through inhibiting complex I is one of the mechanisms proposed for the anti-diabetic action of metformin, which is associated with increased risk of lactic acidosis," the researchers wrote. "In contrast, NEN increases mitochondrial oxidation and is expected to be less likely to associate with the development of lactic acidosis, which is exemplified by the reduction in plasma lactate levels in NEN-treated mice."

The researchers concluded that the excellent safety profile of NEN seen in animal studies may be due to the fact that the drug is rapidly metabolized by the liver, with a half-life of about 1.5 hours. In addition, NEN has relatively poor solubility in water, and it is mostly albumin bound in plasma, which limits extraction to tissues other than the liver.

"Existing toxicology studies have not indicated that either niclosamide or NEN increases body temperature," they wrote...."This outcome is probably due to the mild nature of mitochondrial uncoupling induced by NEN after oral administration and the robustness of body temperature homeostatic regulation in mice."

Principal investigator Shengkan Jin is a founder of Mito BioPharm, which has licensed the patents surrounding the development of niclosamide, ethanolamine, and other mitochondrial uncouplers.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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